Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan.
Oncogene. 2013 Aug 22;32(34):3954-64. doi: 10.1038/onc.2012.428. Epub 2012 Sep 24.
The transcription factor E2F1 has pivotal roles in both cell proliferation and cell death, and is an important molecular target in cancer. Under proliferative conditions E2F1 induces the expression of genes that promote cell cycle progression, such as E2F2, whereas under proapoptotic conditions E2F1 induces expression of genes such as p73 that lead to apoptosis. The mechanism by which the apoptotic function of E2F1 is activated remains unclear, however. We now show that members of the E2F family are covalently conjugated with the ubiquitin-like modifier NEDD8. Overexpression of SENP8, a NEDD8-specific cysteine protease, resulted in deNEDDylation of E2F1 and promoted its transactivation activity at the p73 gene but not at the E2F2 gene. Knockdown of SENP8, on the other hand, attenuated p73 expression and apoptosis induced by E2F1 or by DNA damage. SENP8 also promoted the interaction between E2F1 and its cofactor Microcephalin 1, which is required for p73 induction. These results suggest that NEDDylation is a molecular trigger that modifies the target specificity of E2F1, and could have important implications for E2F1 regulation of apoptosis.
转录因子 E2F1 在细胞增殖和细胞死亡中都具有关键作用，是癌症中的一个重要分子靶标。在增殖条件下，E2F1 诱导促进细胞周期进程的基因表达，如 E2F2，而在促凋亡条件下，E2F1 诱导表达如 p73 等导致细胞凋亡的基因。然而，E2F1 的凋亡功能的激活机制尚不清楚。我们现在表明，E2F 家族成员与泛素样修饰物 NEDD8 共价连接。过表达 NEDD8 特异性半胱氨酸蛋白酶 SENP8 导致 E2F1 的去 NEDDylation，并促进其在 p73 基因上而不是在 E2F2 基因上的转录激活活性。另一方面，SENP8 的敲低减弱了由 E2F1 或 DNA 损伤诱导的 p73 表达和细胞凋亡。SENP8 还促进了 E2F1 与其辅助因子 Microcephalin 1 的相互作用，这是诱导 p73 所必需的。这些结果表明，NEDDylation 是一种分子触发因素，可改变 E2F1 的靶标特异性，并可能对 E2F1 调节细胞凋亡具有重要意义。
